8-hydroxy quinoline derivatives

ABSTRACT

8-Hydroxyquinoline derivatives of the formula 1   WHERE R is hydrogen or methyl X and Y are same or different halogens like chlorine, bromine, or iodine in any two of the position 5,6 and 7 of the quinoline ring are provided according to this invention. These compounds are prepared by reacting a 2halogeno-5-nitrothiazole and the required dihalogen substituted 8-hydroxy quinoline. The compounds of this invention are useful as potent anti the bacterial, antifungal and antiparasitic agent.

United States Patent [191 Somasekhara et al.

[ Dec. 31, 1974 S-HYDROXY QUINOLINE DERIVATIVES [52] US. Cl 260/283 S, 260/289 QX, 260/302,

424/258 [5 1] Int. Cl C07d 33/36 [58] Field of Search 260/283 S, 289 QX, 302 R [56] References Cited 7 UNITED STATES PATENTS 7/1972 Moore et aL 260/302 R OTHER PUBLICATIONS Morrison and Boyd; Organic Chemistry, 1959, p. 412.

' Primary Examiner-Donald G. Daus Assistant Examiner-Mary C. Vaughn Attorney, Agent, or Firm-Ladas, Parry, Von Gehr, Goldsmith & Deschamps [57] ABSTRACT 8-Hydroxyquinoline derivatives of the formula 1 where R is hydrogen or methyl X and Y are same or different halogens like chlorine, bromine, or iodine in any two of the position 5,6 and 7 of the quinoline ring are provided according to this invention. These compounds are prepared by reacting a 2-halogeno-5- nitrothiazole and the required dihalogen substituted 8-hydroxy quinoline. The compounds of this invention are useful as potent anti the bacterial, antifungal and antiparasitic agent.

6 Claims, No Drawings 1 8-HYDROXY QUINOLINE DERIVATIVES This invention relates to novel 8-hydroxy-quinoline derivatives, a process for their preparation and pharmaceutical compositions containing same. 5

It is an object of this invention to porpose novel 8- (axkalimetal) hydroxyquinoline derivatives and a process for the In preparation of Same where R, X and Y are as defined before.

It is another object of the invention to Propose new reafcn-On can cargled Outm the presence of a pharmaceutical compositions having the novel comgggg ermg orgamc so vent at temperatures below pounds of this invention. and ilbove room tempFratulie' it is, in particular an object of this invention to pro- The alkali metal preferred is sodium or potassium m v the compound of formula ill. pose s'bydroxyqumohpe delilYanves f The halogen preferred in the compound of formula lgjgizrsisakoanggglgralgrlgrggtiparasltic properties and a if chlorine bromina I l b s non-inter ermg organic so vents mention may e of or ing the novel compounds of this inventioii to be useful methyl sulfoxide though others are useful the only CH7 teria being that the solvent used should be a nonas potent antibacterial, antifungal and antiparasitic interfering type compositions against various bacterial, fungal and par- The reaction canbe i d t at temperatures in asmc dlse.ases' 1 the range of 40 100C for about 60 minutes to 7 Accordmg.to i there provlded novel hours though these are not very critical for the reac- S-hydroxyqumohne derivatives of formula 1 tion.

X The obtained products may be purified, if required, by recrystallisation using for example benzene-hexane Y as solvent.

As novel compounds of this invention the following may be mentioned for illustration purposes only and is N not intended to mean any restriction thereof.

8-(S-Nitrothiazolyl-Z-oxy)-5,7-dichloro-quinoline i 8-(S-Nitrothiazolyl-Z-oxy)-5,7-dibromo-quinoline N02 I 8-(S-Nitrothiazolyl-Z-oxy)-5,7-diiodo-quinoline 8-(5-Nitrothiazolyl-2-oxy)-5,7-dibromo-2-methylwherein R is hydrogen or methyl, X and Y are same or qHmQhne different halogens like chlorine, bromine or iodine in fl F any two of the positions 5, 6 and 7 of the quinoline ring. qumolme This invention also provides a process for the manu- It has found b us h novel facture of novel 8-hydroxyquinoline derivatives of forhydroxyqumolm? of i mvemlon mula I defined above which comprises reacting a 40 iami'bactenai anti-fungal and z halogene s nitrothiazole of formula [I parasitic propert es as compared to known 8-hydroxy qumolme derivatives. The known derivatives have not Hal yielded satisfactory results particularly due to their side KS effects. The compounds of this invention are found to be sat- =K isfactory in the above respect. N02 11 For a better understanding of the properties of the compounds of the invention, detailed biological studies where the halogen in the second position is chlorine of these compounds were carried out and compared or bromine, with an alkali metalsalt f th i d with those ofQuixalin under similar conditions. The dihalogen substituted 8-hydroxy quinoline of formula results of some of these comparative studied are pres- III ented in the Table 1 attached.

TABLE 1 Antimicrobial activity (in vitro) Organisms/MIG values in, mcgJml.

Compound M.P., Reference No., A/R S. 1 Pa. vul- Pa. ueru- X Y R 0. Example No. S. aureus aureus E. coli S. ahigae S. typhi garis genose 5-Cl 7-Cl H 122. 4 SEC 1111, EX. 12 0. 5 0. 5 5-10 0. 5 5.0 5. 0 2. 0 5-Br 7-Br H -3 SRO 1128, EX. 3.. 5. 0 y 5. 0 10-0 5.0 10. 0 5.0 20. 0 5-131- 7-Br CH 119-121 SRO 1134, EX. 5 0.5 0.5 10. 0 0.5 10. 0 10. 0 10.0 5-01.... 7-Cl CH; 127-9 SRC 1277 0.5 0. 5 5-10 0. 5 5. 0 10. 0 10.0 Quixalin 5 1-5 5 5 5 5 20 Ta le 1 9 1011295 Compound Antifungal activity, organisms/MIC values in mcgJml. Antituberculous activity My. tuber- Tr. men- Ph. culosis MIC M.1., Reference No., C. tagro- M. jeim- N-ast- Asp. values in, X Y R 0. experiment No. albicana ph tea gypsum selmz teroide fumigatus mcgJml.

II 122. 4 SRO 1111, EX. 1-2- 1. 0 5. 0 5.0 20. 0 5-10 5 20.0 11 130-3 SRC 1128, Ex. 3 1. 0 1. 5 5. 0 5. 0 5. 0 5.0 20.0 CH3 119-21 SRO 1134, Ex. 5--- 1.0 5.0 5.0 5.0 -20 5.0 CH 3 127-9 S RC 1277 1-5 15 1-5 5-10 -50 -50 5 5 5 5 The results shown in Table 1 will give an idea of the potent antibacterial and antifungal properties of the compounds of the invention.

The compounds of this invention can be used either alone or in conjunction with suitable pharmaceutically acceptable carriers therefor. It is also possible to employ either a single active compound of this invention or a combination of two or more active compounds as is found expedient.

As pharmaceutically acceptable carriers, conventional solid and liquid carriers can be used and suitable formulations can be in the form of liquids, dusts, tablets. granules, emulsifiable concentrates and wettable powders etc.

The different formulations can be prepared by well known techniques. For example liquid formulations can be prepared by dissolving the active ingredient/s in a suitable pharmaceutically acceptable liquid carrier or diluent with or without the use of known adjuvants like conventional emulsifying agents, wetting agents or dispersing agents etc.

It is possible, as stated before, to use the active compound alone in required doses. However, in the formulations, the concentration of the active ingredient/s may normally be a minimum of 1.0% by weight to a maximum of 60.0% by wt., the preferred range being, 25 to 60% though the amounts of the active ingredient/s depend on the type and severity of the disease, the form of the composition, the type of the active ingredient etc.

The invention will now be explained with reference to the following examples which are by way of illustration only and do not mean any restriction thereof.

EXAMPLE 1 EXAMPLE 2 8-(5-Nitrothiazolyl-2-oxy)-5,7-dichloroquinoline (SRC Potassium salt of 5,7-dichloro-8-hydroxyquinoline (2.5 g; 0.01 mole) and 2-bromo-5-nitrothiazole (2.1 g; 0.01 mole) were refluxed in ethylmethyl ketone (50 ml) for 3 hours. The solvent was distilled off in vacuo.

The residue was triturated with sodium acetate solution (3 g in 100 ml). The insoluble material was crystallised from benzene-hexane to botain the title product melting at l2224C. Yield 2.9 gms.

EXAMPLE 3 8(5-Nitrothiazolyl 2-oxy)-5,7-dibromoquinoline (SRC 1128) Sodium salt of 5,7 dibromo-8-hydroxyquinoline (6.5 g; 0.02 mole) and 2-bromo-5-nitrothiazole (4.2 g; 0.02 mole) were taken in dimethylsulphoxide (10 ml) and heated at 5060C for 3 hours. The reaction product was cooled and diluted with water 100 ml) and sodium bisulphite (l g). The gummy solid was separated by decantation. It was taken into benzene. The benzene phase was washed with 1% sodium bisulphite solution (100 ml), 2% sodium acetate solution (100 ml) and then with water. The benzene phase was dried over sodium sulphate, concentrated and diluted with hexane to obtain the crude title product. It was crystallised from benzene-hexane m.p. l3l33C. Yield 6.7 gm.

(SRC

, hours. The solvent was removed in vacuo. The residue was taken in benzene ml) and washed with 1% sodium bisulphite solution (100 ml), 2% sodium acetate solution (100 ml) and then with water. The benzene phase was dried over sodium sulphate, concentrated to one-fourth of the volume and then diluted with hexane to obtain the crude title product. It was crystallised from benzene-hexane; m.p. 37C. Yield 7.3 grams.

EXAMPLE 5 8-(S-Nitrothiazolyl-Z-oxy)-5,7-dibromo-2methylquinoline (SRC 1134) Sodium salt of 5,7-dibromo-2-methyl-8- hydroxyquinoline (6.8 g; 0.02 mole) and 2-chloro-5- nitrothiazole (3.3 g; 0.02 mole) were taken in absolute ethanol (100 ml) and refluxed for 5 hours. The solvent was distilled off in vacuo; the residue was taken in benzene (100 ml) and washed with 1% sodium bisulphite solution (100 ml), 2% sodium acetate solution (100 ml) and then with water. Yield 6.3 gms.

The benzene phase was dried over sodium sulphate, concentrated to 20 ml and diluted with hexane to obtain the crude title product; it was crystallised from benzene-hexane; m.p. 1l9-21C.

We claim:

1. 8-Hydroxyquinolines of the formula 1 Y I l. \o yv.

wherein R is H or methyl, X and Y are the same or different halogens like, chlorine, bromine or iodine in any two ofthe positions and 7 ofthe quinoline ring. 

1.8-HYDROXY QUINOLINES OF THE FORMULA I
 2. The compound according to claim 1 wherein X and Y are 5,7-dichloro and R is hydrogen.
 3. The compound according to claim 1 wherein X and Y are 5,7-dibromo and R is hydrogen.
 4. The compound according to claim 1 wherein X and Y are 5,7-diiodo and R is hydrogen.
 5. The compound according to claim 1 where in X and Y are 5,7-dibromo and R is methyl.
 6. The compound according to claim 1 wherein X and Y are 5,7-dichloro and R is methyl. 